The idiopathic inflammatory myopathies include polymyositis (PM), dermatomyositis (DM), necrotizing myositis (NM) and inclusion body myositis (IBM), and together affect greater than 75,000 Americans. The correct diagnosis of IBM is especially important, since this disorder is unresponsive to immunosuppressive therapies, which have serious side effects. The gold standard for IBM diagnosis is muscle biopsy, but anatomic and temporal heterogeneity of the disorder greatly limits its sensitivity and specificity. Moreover biopsy is an invasive surgical procedure, and not appropriate for repeated monitoring of disease evolution and treatment response. There are no reliable serum biomarkers for IBM. An explosion of basic research has identified key regulatory RNAs, including microRNAs and long non-coding RNAs (lncRNAs) that have essential roles in muscle differentiation and regeneration. These RNAs are released into the extracellular space, reaching the bloodstream and other body fluids in very stable forms, due to both membrane encapsulation and protein binding. Because muscle makes up nearly half of the total body mass, its RNAs and their metabolic products contribute a large component to body fluids, including serum and urine. Our preliminary data indicates that muscle- specific microRNAs can be detected in human serum. The objective of the proposal is to identify a small panel of RNA biomarkers for the sensitive, specific and non-invasive diagnosis of inclusion body myositis. This will be accomplished by the completion of two specific aims. Aim 1: Discovery and validation of non-coding RNAs that distinguish inclusion body myositis from other idiopathic inflammatory myopathies. Aim 2: Verification and validation of selected non-coding RNAs as non-invasive serum and/or urine biomarkers of inclusion body myositis. Discovery of sensitive and specific tissue biomarkers of inclusion body myositis in Aim 1 would fill a critical, unmet need in the myositis field, regardles of whether these markers are found to be reliable biomarkers in patient serum or urine (Aim 2).